title: Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM.
  
  
  RESULTS
  We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3.
  
  
  CONCLUSIONS
  The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University.
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: Ryu
authors.initials: R
authors.lastname: Takeya
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Yamano
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsuo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nomura
authors.forename: Hideki
authors.initials: H
authors.lastname: Sumimoto
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D044466:Asian People; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000080865:Formins; D006801:Humans; D007564:Japan; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism
chemical_list: C485994:FHOD3 protein, human; C579478:Fhod3 protein, rat; D000080865:Formins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D026362:Serum Response Factor